These studies demonstrate that HRV-neutralizing antibodies in both nasal wash and serum are low seven days after HRV inoculation, and their titers begin to rise at approximately two weeks after inoculation[44], although it should be mentioned that the conventional detection assessments used in these studies might be less sensitive in detecting HRV-specific antibodies than the assessments that are used nowadays. HRV-16 or placebo. One week later, all subjects received HRV-16. Baseline seronegative subjects (n = 18) were included for further analysis. Results Contamination rate was 82%. Main HRV contamination induced a marked increase in viral weight and IP-10 levels in nasal wash, while a similar pattern was observed for IL-6 and IL-10. Apart from an increase in IP-10 plasma levels, HRV infection did not induce systemic immune effects nor lower respiratory tract inflammation. With comparable viral weight present during the second HRV challenge, IP-10 and IL-6 in nasal wash showed no increase, but gradually declined, with a similar pattern for IL-10. Conclusion Upon a second HRV challenge one week after the first, a less pronounced response for several innate immune parameters is observed. This could be the result of immunological tolerance and possibly increases vulnerability towards secondary infections. Introduction In the recent decade, it has become obvious that bacterial sepsis may induce an immunosuppressed state called sepsis-induced immunoparalysis[1, 2], a form of immunological tolerance which renders the host unable to obvious primary infections leading to increased vulnerability towards secondary infections[3]. This immunologically tolerant state is characterized by both innate as well as adaptive immunodysfunction, such as functional defects in leukocytes, Diphenidol HCl downregulation of cytokines and immunostimulatory membrane-bound receptors, accompanied by the upregulation of unfavorable costimulatory molecules[3, 4]. A similar phenomenon is observed with virulent respiratory computer virus infections, such as influenza, which predispose to secondary bacterial or fungal infections[5, 6]. Human rhinoviruses (HRVs) are the most frequent cause of the common chilly[7, 8] with prevalence estimates as high as 80% of the adult populace[9]. HRV contamination results in the production of inflammatory cytokines and chemokines[10C14], and subsequent recruitment of immune Diphenidol HCl cells into the nasopharyngeal[15] and bronchial mucosa, and secretions[11C14]. In addition, HRV-specific neutralizing antibodies are produced, resulting in seroconversion approximately 28 days later[11, 16]. HRVs consist of three species, HRV-A, HRV-B and the more recently discovered HRV-C[7]. Due to its high virulence, HRV-C can cause systemic and severe respiratory infections in previously healthy subjects[7]. This has mainly been reported for children, although several adult cases have also been explained[7, 17]. Although HRV-A and HRV-B may Diphenidol HCl cause severe infections in young children, immunocompromised patients, and/or patients with pre-existing respiratory diseases[18C21], it is unknown to what extent these species induce systemic immunological effects or lower respiratory tract disease in healthy adult subjects. Furthermore, although studies indicate that HRV can also induce immunosuppressive or tolerance mechanisms[22, 23], this has by no means been investigated in humans studies that have shown that HRV can induce immunosuppressive mechanisms[22, 23]. The effects observed in the present study are reminiscent of endotoxin tolerance, observed after challenging healthy volunteers with bacterial lipopolysaccharide[36, 37], and might resemble some aspects of the severely immunosuppressed state observed in patients with sepsis[3] and influenza infections[5]. As such, it is tempting to speculate that previous contamination with relatively moderate viruses such as HRV renders patients increased vulnerable towards secondary bacterial and/or viral infections. However, additional studies are warranted to assess the clinical relevance of our observations. The tolerance effect observed could be due to desensitization effects on local immune cells or a type-I interferon induced CD8 T-cell mediated anti-viral state where no replication occurs[38]. For instance, it was shown that HRV can survive in alveolar macrophages and impair the cytokine responses to a second challenge with bacterial ligands[23]. Along these lines, for influenza and respiratory syncytial Rabbit polyclonal to SLC7A5 computer virus (RSV), previous work has exhibited a post-viral desensitization of alveolar macrophages to Toll-like receptor (TLR) ligands, associated with reduced NF-kappaB activation and chemokine production[5]. In our study, we only included seronegative subjects, because previous work has exhibited that serostatus alters both HRV-induced symptom scores[16, 39] as well as the HRV-induced immune response, which we showed to be virtually nullified in seropositive subjects[29]. As such, next to the pathophysiological effects, our Diphenidol HCl results show that a crossover design is usually neither feasible using a short interval, Diphenidol HCl due to a suppressed innate immune response, nor using a longer interval, due to antibody formation that starts approximately one week after HRV contamination[16] and severely impacts the immune response[29]. The mucosal immune response observed in the present study, reflected by the increase in cytokines in nasal wash, is in line with numerous previous and studies[11C13, 40]. In response to HRV contamination, IP-10 was in contrast to other cytokines, produced in nasal wash of all subjects following contamination. As such, our results are in accordance with previous studies that have.